Different contribution of class IIHLA in fulminant and typical autoimmune type 1 diabetes mellitus

Aims/hypothesis: Fulminant type 1 diabetes, which is characterised by a markedly acute onset of diabetes and an absence of islet-related autoantibodies, accounts for 20% of type 1 diabetes in Japan. We aimed to clarify the contribution of the HLA subtype to fulminant type 1 diabetes in Japanese. Methods: We determined the serological subtypes of HLA- A, - DR and - DQ in 115 patients with fulminant type 1 diabetes, 98 patients with typical type 1A diabetes and 190 normal control subjects. Results: The frequency of HLA- DR4, but not DR9, was significantly higher in fulminant type 1 diabetes, while those of HLA- DR1, DR2, DR5 and DR8 were significantly lower than those in controls. In contrast, DR9 but not DR4 was more frequent and DR2 was extremely rare in typical type 1A diabetes. Haplotype analysis revealed that DR4- DQ4 was significantly more frequent, and both DR2- DQ1 and DR8- DQ1 were less frequent in fulminant diabetes. In type 1A diabetes, DR2- DQ1 was extremely rare while DR9-DQ3 was significantly more frequent. In the combination analysis, the homozygotes of DR4- DQ4 in fulminant type 1 diabetes and DR9- DQ3 in typical type 1A diabetes indicated high odds ratios ( 13.3 and 13.3, respectively). Conclusions/ interpretation: Our results suggest that class II HLA contributes to the development of fulminant type 1 diabetes. Susceptibility and resistance of the HLA subtype to type 1 diabetes are distinct between fulminant and typical autoimmune type 1 diabetes.